三阴性乳腺癌（TNBC）是一种特殊类型乳腺癌，约占所有乳腺癌的15%，缺乏内分泌和HER2治疗靶点，目前尚无有效的治疗方法。靶向肿瘤间质是肿瘤治疗新策略之一。成纤维细胞激活蛋白（Fibroblast Activation Protein, FAP）特异表达于90%的上皮性肿瘤间质的成纤维细胞表面，与肿瘤发生发展、免疫逃逸、化疗耐药以及患者预后密切相关，因而，可作为TNBC治疗靶点。前期工作中，我们从噬菌体全人抗体库中筛选到1株高亲合力的FAP抗体，且与小鼠FAP有交叉免疫反应；同时，建立了多种抗体-化疗药物的偶联方法。在此基础上，本项目拟将FAP抗体和强烈微管抑制剂美登素偶联，构建一种新型的靶向化疗偶联物，以期能靶向杀伤成纤维细胞和旁杀伤肿瘤血管内皮细胞及肿瘤细胞，从而发挥抗肿瘤作用，利用细胞和动物实验评价其抗肿瘤活性，探讨作用机理，为三阴性乳腺癌靶向治疗药物的研发奠定基础。

Triple negative breast cancers(TNBC) is a specific breast cancer which accounts for about 15% of all breast cancers. Now, the absence of the targets of endocrine and HER2 leads to difficulty in the treatment of TNBC. Targeting tumor stroma is one of the new choices used in this kind of treatment. Fibroblast Activation Protein (FAP) expresses on the surface of fibroblasts of more than 90% of epithelial tumors and is closely related to tumor formation and development, tumor immnunoescape, chemotherapeutic resistance, and patient prognosis. So, it is suitable to be a target of TNBC treatment. During our preliminary work, a high- affinity FAP antibody, which has cross immunoreactions with rat FAP, was screened out from phage-displayed library of human. Meanwhile, many coupling methods of antibody- chemotherapeutics were also established. Based on these factors, in this project, a new kind of targeted chemotherapy conjugate will be constructed by the coupling of FAP antibody and microtubule inhibitor, Maytansine, so as to achieve the targeted killing of tumor associated fibroblasts and bystander killing of vascular endothelial cells and tumor cells. What`s more, cell experiment and animal experiment will be performed to assess the anticancer activity and its anti-cancer mechanism. This helps to make better foundation for the development of targeted chemotherapy of TNBC cancers.